Aliphatic esters of 3, 4-bis-(mu-methyl-p-hydroxyphenyl)-2, 4-hexadiene



Patented Mar. 14, 1950 UNITED STATES ATENT OFFICE ALIPHATIC ESTERS OF3,4-BIS- (m-METHYL- p-HYDROXYPHENYL) -2,4-HEXADIEN E Victor Niederl;Round Top, N. Y., and Albert Bloom, Summit, N-.1' J., assignors to Reed& Carnrick, Jersey City, N.:J., a corporation of New Jersey No Drawing.Application December 17, 1946, Serial No. 716,884

The present invention relates to certain esters ofdialkyldihydroxydiphenylhexadiene, wherein hexadiene containing 2 to 4carbon atoms in the.

carboxylic acid radicals.

This application isa continuation-in-part of application Serial No.524,090, filed February 26, 1944, now Patent No. 2,419,516, dated April22, 1947, and 696,050, filed September 10, 1946.

It is an object of this invention to providea number of new estrogeniccompounds of high estrogenic activity and. low toxicity.

It is a special object of this invention to produce certain estrogenicsubstances which, be-

cause of their high estrogenic activity and low.

toxicity, exhibit and possess very favorable thera-' peutic indices; andwhich, additionally, possess fying the said mixture ofalkylhydroxypropiophenones with a suitable organic esterifying reagent,and then fractionally distilling the reaction product under reducedpressure to separate the ortho and paraacyloxy derivatives; (D)pinacolizing the alkyl-p-acyloxyphenone by slowly introducing water intoan isopropyl ether solution of the same in the presence of amalgamated:

aluminum, thereby producing a SA-bis-(alkyl-pacyloxyphenyD-3Ahexanediol; and (E) converting the hexanediol structure of the lastmentioned compound to a hexadiene structure by dehydrating the same witha mixture of acetic acid anhydride and acetyl chloride, thereby forminga 3,4 -bis (alkyl-p-acyloxyphenyl) 2,4 -hexadiene.

The esters of 3,4-bis-(alkyl-p-hydroxyphenyll- 2,4-hexadiene may also beproduced by appropriate saponification of a 3,4-bis-(alkyl-p-acyloxyphenyl)-2,4-hexadiene to the correspondingBA- bis-(alkyl-p-hydroxyphenyl) -2,4-hexadiene,. and

4 Claims. (Cl. 260-479) then reacting either or both of the phenolichydroxyl groups with the desired acylating reagent by variousesterifying methods known to the art.

Collectively the preferred estrogenic compounds of this invention may bereferred to by the followingformula:

wherein X and X are methyl groups, and at least one Y is an acyl radicalderived from a saturated aliphatic carboxylic acid of 2 to 4 carbonatoms, and the other Y is a hydrogen or the same or a difierent acylradical. In the simpler and more easily produced compounds, Y and Yrepresent the same acyl radical. From the above formula it is obviousthat the methyl groups X and X and the acyl radicals Y and Y may havetheir positions designated as 3' and 4', respectively, or as meta (m)and para (p), respectively. It will be understood that reference hereinto saturated'aliphatic carboxylic acid esters of 3,4-bis-(m-methyl-p-hydroxyphenyl) -2,4-hexadiene containing from 2 to 4carbon atoms in the carboxylic acid radical refers to all types ofesters included in the illustrative formula.

Example 1 A. Molar quantities of o-cresol and propionyl chloride areallowed to react in a suitable contion.

B. Thirty grams of the above crude o-methylphenyl propionate isdissolved in milliliters of dry nitrobenzene and chilled in an ice bathafter which 35 grams of anhydrous aluminum chloride is added in smallportions. The reaction mixture is I kept cold during the addition ofaluminum chloride, after which it is left standing in an ice bath forseveral hours and then at room temperature overnight. Thereafter, thereaction mixture is decomposed with ice Water, a few milliliters ofhydrochloric acid are added, and the reaction mixture is extracted withether. The :nitrobenzene-ether solution is washed with water and thenextracted with 10 per cent sodium hydroxide solution. Finely crushed iceis added to this alkali solution which is then acidified withhydrochloric acid. The precipitate formed is collected and subjected tosteam distillation to remove the ortho isomer. The remaining m methyl phydroxypropiophenone may be used for the next reaction without furtherpurification.

C. Twenty grams of the above ketone is added to 40 grams of amalgamatedaluminum foil covered with one liter of moist ether and refluxed forseveral hours. After standing overnight, the reaction mixture isfiltered, and the residual magma is washed well with ether. The ethersolutions are combined and concentrated by removing most of the ether,after which the residue is placed in the refrigerator for several daysto allow it to solidify. The crystalline product is then collected andwashed with a small portion of cold acetic acid. After recrystallizationfrom ethanol the 3,4-bis-(m-methyl-p-hydroxyphenyl)-3,4-dihydroxyhexanemelts at 182 to 183 C.

D. Five grams of the above glycol is suspended in 15 milliliters ofacetic acid anhydride, and milliliters of acetyl chloride is added. Theflask is placed in a water bath which is gradually heated to 70 C., andheating at this temperature is continued for about twenty minutes. Theflask is chilled, and the reaction mixture is treated with finelycrushed ice. The recipitate obtained is recrystallized from ethanol, andthen the Bil-bis- (m-rnethyl-p-acetoxyphenyl)-2,4-hexadiene has amelting point of 166 to 168 C, The SA-bis- (m-methy1-p-acetoxyphenyl)-2,4-hexadiene produces 63% estrus in ovariectomized rats when givenorally in a dosage of gammas.

Example 2 A. One mol of o-cresol and 1.05 mols of propionic acidanhydride are placed in a suitable reaction vessel provided with areflux condenser. The mixture is then heated to the point of reflux andallowed to reflux for two hours. Propionic acid formed during thereaction and any surplus propionic acid anhydride are removed bydistillation, and the residual o-cresyl propionate remaining at 175 C.is subjected to the next step without further purification. (Whereo-cresyl propionate is available, this step may be omitted.)

B. One and one-half mols of anhydrous aluminum chloride is dissolved in400 milliliters of dry nitrobenzene in a suitable vessel provided withan eflicient stirrer, and the system is cooled by an appropriate coolingbath to C. The crude o-cresyl propionate from step A is then addedgradually, and stirring is continued for two hours, during which timethe temperature of the reaction is kept between 20 and C. After thistime the reaction vessel is equipped with an absorption tube to preventingress of moisture and allowed to stand at room temperature for 24hours. Then the reaction mixture is gradually poured with constantstirring into three times its volume of 1% hydrochloric acid in icewater and the water-nitrobenzene system is allowed to stand until a goodseparation has taken place. The nitrobenzene layer, which containsmmethyl-p-hydroxypropiophenone and m-methylo-hydroxypropiophenone isdrawn oil, and the aqueous layer is extracted once with about onehalfits volume of isopropyl ether. This ether extract is added to thenitrobenzene solution, which is then diluted with twice its volume ofisopropyl ether. This solution is washed once with water and thenextracted twice with an equal volume of 10% sodium hydroxide solution.This alkaline solution is washed once with one-fourth its volume ofisopropyl ether, cooled to about 10 C., subjected to eificient agitationand gradually acidified with hydrochloric or sulfuric acid to Congo red.The crystalline product which thus precipitates is then filtered off,washed with distilled water until the washings are neutral to litmus,and dried.

C. The above solid material, consisting of approximately ofm-methyl-p-hydroxypropiophenone and about 20% of the o-hydroxy isomer,is placed in a 500 milliliter round-bottom flask provided with a refluxcondenser, 1.05 mols of propionic acid anhydride is added, and thereaction mixture is refluxed for two hours. The material is thentransferred to a suitable vacuum distilling flask and fractionallydistilled. Fractions distilling below C. at 21 millimeter Hg pressureare discarded. The unwanted o-propionoxy compound distills largely at140 to C., and 21 millimeter pressure, and them-methyl-p-propionoxypropiophenone distills at -185" C., and 21millimeter pressure. Thus, because of the wide divergency between theboiling points of the two isomers, separation is easily eiiected.Melting point of the m-methyl-ppropionoxypropiophenone is 50-52 C. Theyield, based on 108 grams of starting o-cresol, is at least 80 grams.

By using other acid anhydrides or acid halides, other esters ofm-methyl-p-hydroxypropiophenone may be prepared and isolated in asimilar manner.

D. Sixty grams of oil-free aluminum foil is shaken for five minutes with100 milliliters of 5% mercuric chloride solution in a 3 literroundbottom flask. The mercuric chloride solution is then poured off andthe aluminum foil is washed successively with water, methanol andisopropyl ether. Immediately after the last washing, the 80 grams ofm-methyl-p-propionoxypropiophenone from the preceding step, dissolved in800 milliliters of isopropyl ether, is added to the amalgamatedaluminum. The flask is then provided with a sealed stirrer, a refluxcondenser and a dropping funnel. While constantly stirring, water isallowed to enter the system slowly so that the temperature of thereaction mixture does not rise above 50 C. After 130 milliliters ofwater hasbeen introduced over a period of about two hours, the stirringis continued until practically all of the amalgamated aluminum has beenconverted into aluminum hydroxide and mercury. About 800 milliliters ofwater is then added to the magma-like reaction mixture, the mass is wellagitated, transferred to a separating funnel, and the upper ethereallayer separated. The aluminum hydroxide magma is washed once with aboutone-fourth its volume of isopropyl ether, and the ether solutions arecombined and filtered. The combined solutions are subjected tolow-temperature distillation to remove the isopropyl ether. Theremaining viscous oil which contains the desired compound, 3,4-bis-(mmethyl-p-propionoxyphenyl)-3,4-hexanediol, is refrigerated to allow itto crystallize, or it can be used in its oily consistency for the nextstep. (When permitted to crystallize, and then recrystallized fromethanol, this compound has a melting point of 151-153 C.)

By using other esters of m-methyl-p-hydroxypropiophenone instead ofpropionate, other 3,4- bis-(m-methylp -acyloxyphenyl) -3,4-hexanediolscan be readily prepared.

E. Eighty grams of theB/l-bis-(m-methyl-ppropionoxyphenyl)-3,l-hexanediol, either in its oilyconsistency or in crystalline form, is placed in a 500 milliliterround-bottom flask along with 130 milliliters of acetic acid anhydrideand 100 milliliters of acetyl chloride. The reaction mixture is gentlyrefluxed for 30 minutes, allowed to cool, and then poured into twice itsvolume of water at C. After allowing to stand with occasional sthringfor one hour, the water is decanted and the residue is treated with 5%NazCOs solution until the mixture is rendered permanently alkaline. Theaqueous solution is discarded, after which the residue is washed twicewith water. Finally the semi-crystalline mass is triturated with icecold methanol, and the resulting white crystalline material is filteredoff, washed once more with cold methanol, again filtered and allowed todry. Upon recrystallization, the 3,4-bis-(m-methyl p propionoxyphenyl)ZA-hexadiene has a melting point of 139-140 C. The overall yield by thisprocess, starting with 108 grams of o-cresol, is about 30 grams.

Administered orally to ovariectomized rats according to standardprocedure, gammas of 3,4-bis-(m-methyl p propionoxyphenyl)-2,4-hexadiene produces 83% estrus.

It will be obvious from the above example that a variety of esters, suchas may be preferred as the estrogenic end product for use in thetreatment of the menopausal syndrome, may be prepared in a like manner.

Example 3 A. Two grams of3,4-bis-(m-methyl-p-propionoxyphenyD-Z-hexadiene is dissolved in 10milliliters of Claisen solution and heated on the water bath until ithas completely dissolved. After standing at room temperature fortwenty-four hours, this solution is diluted with 40 milliliters ofdistilled water, filtered, and then gradually acidified with 10 per centhydrochloric acid, to Congo red. The precipitate is allowed to solidify,filtered off, washed with water and placed on porous tile to dry. Afterrecrystallization from 50% ethanol the3,4-bis-(m-methyl-p-hydroxyphenyl) -2,4-hexadiene melts at 187 to 189 C.

B. One gram of 3,4-bis-(m-methyl-p-hydroxyphenyl)-2,4-hexadiene isdissolved in 10 milliliters of anhydrous pyridine; 2.5 milliliters ofbutyric anhydride is added, and the mixture is refluxed gently for twoand a half hours. After cooling, the reaction mixture is treated withwater, and the solid which separates after a while is collected. The3,4-bis-(m-methyl-p-butyroxyphenyl)-2,4-hexadiene thus obtained iswashed with water and recrystallized from methanol; the melting point is1 3 to 124 C.

Employing the above 3,4-bis-(m-methyl-p-hydroxyphenyl) -2,4-hexadiene,and by varying the molar ratios of phenolic compound and esterifyingreagent, as well as using other acid halides 6 or anhydrides, otheresters including monoesters as well as diesters and mixed esters, may beprepared.

The monoesters may also be produced from the diesters by knownhalf-saponification methods.

We have found that the estrogenic compounds provided as examples hereincan be administered orally, without observable'toxic effects, in doseswhich exceed many times their efiectiveestrogenic doses. The estrogenicpotencies of the compounds of this invention may be readily appreciatedwhen it is recognized that, whereas oral administration of 50 gammas ofestrous produces only about per cent estrus in ovariectomized rats, oneof the above compounds, for example, namely 3,4-bis-(m-methyl-p-propionoxyphenyl) 2,4-hexadiene, produces 83 per cent estrusin ovariectomized rats when given orally in 15 gamma doses. Theestrogenic potency of the compounds of this invention is furtherdemonstrated by the results of clinical experiments which disclose thatthe ordinary symptoms in the average menopausal patient are markedlyalleviated through the oral administration of 5 milligrams of3,4-bis-(m-methyl-p-,acetoxyphenyl) -2,4-hexadiene per day.

It will be understood that the discussion of the estrogenic potency andthe unusual freedom from toxicity of certain of the compounds of thisinvention is merely illustrative of the properties generally possessedby the other compounds specifically disclosed herein.

It will be understood further that the embodiments of our inventiondescribed in the specification and in the examples are only illustrativeof the compounds and the processes by which they are produced. Variousmodifications can be made without departing from the principles of theinvention or the scope of the invention which is defined in the claims.

We claim:

1. A new class of compounds, saturated monobasic unsubstituted aliphaticcarboxylic acid esters of 3,4-bis-(m-methyl-p-hydroxyphenyl) -2,4-hexadiene containing 2 to 4 carbon atoms in the acyl radical.

2. A new compound, 3,4-bis-(m-methyl-pacetoxyphenyl) -2,4-hexadiene.

3. A new compound, 3,4-bis-(m-methyl-ppropionoxyphenyl) -2,4=-hexadiene.

new compound, 3,4-bis-(m-methyl-pbutyroxyphenyl) -2,4-hexadiene.

- VICTOR NIEDERL.

ALBERT BLOOM.

REFERENCES CITED FOREIGN PATENTS Country Date Switzerland Nov. 15, 1941Number

1. A NEW CLASS OF COMPOUNDS, SATURATED MONOBASIC UNSUBSTITUTED ALIPHATICCARBOXYLIC ACID ESTERS OF 3,4-BIS-(M-METHYL-P-HYDROXPHENYL)-2,4HEXADIENECONTAINING 2 TO 4 CARBON ATOMS IN THE ACYL RADICAL.